This invention is directed to substituted anilides, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of cell adhesion.
Cell adhesion is a process by which cells associate with each other, migrate towards a specific target or localise within the extra-cellular matrix. Many of the cell-cell and cell-extracellular matrix interactions are mediated by protein ligands (e.g. fibronectin, vitronectin and VCAM-1) and their integrin receptors [e.g. VLA-4 (xcex14xcex21)]. Recent studies have shown these interactions to play an important part in many physiological (e.g. embryonic development and wound healing) and pathological conditions (e.g. tumour-cell invasion and metastasis, inflammation, atherosclerosis and autoimmune disease).
A wide variety of proteins serve as ligands for integrin receptors. In general, the proteins recognised by integrins fall into one of three classes: extracellular matrix proteins, plasma proteins and cell surface proteins. Extracellular matrix proteins such as collagen fibronectin, fibrinogen, laminin, thrombospondin and vitronectin bind to a number of integrins. Many of the adhesive proteins also circulate in plasma and bind to activated blood cells. Additional components in plasma that are ligands for integrins include fibrinogen and factor X. Cell bound complement C3bi and several transmembrane proteins, such as Ig-like cell adhesion molecule (ICAM-1,2,3) and vascular cell adhesion molecule (VCAM-1), which are members of the Ig superfamily, also serve as cell-surface ligands for some integrins.
Integrins are heterodimeric cell surface receptors consisting of two subunits called xcex1 and xcex2. There are at least twelve different xcex1-subunits (xcex11-xcex16, xcex1-L, xcex1-M, xcex1-X, xcex1-IIb, xcex1-V and xcex1-E) and at least nine different xcex2 (xcex21-xcex29) subunits. The integrin family can be subdivided into classes based on the xcex2 subunits, which can be associated with one or more xcex1-subunits. The most widely distributed integrins belong to the xcex21 class, also known as the very late antigens (VLA). The second class of integrins are leukocyte specific receptors and consist of one of three xcex1-subunits (xcex1-L, xcex1-M or xcex1-X) complexed with the xcex22 protein. The cytoadhesins xcex1-IIbxcex23 and xcex1-Vxcex23, constitute the third class of integrins.
The present invention principally relates to agents which modulate the interaction of the ligand VCAM-1 with its integrin receptor xcex14xcex21 (VLA-4), which is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils.
The integrin xcex14xcex21 mediates both cell-cell and cell-matrix interactions. Cells expressing xcex14xcex21 bind to the carboxy-terminal cell binding domain of the extracellular matrix protein fibronectin, to the cytokine-inducible endothelial cell surface protein VCAM-1, and to each other to promote homotypic aggregation. The expression of VCAM-1 by endothelial cells is upregulated by proinflammatory cytokines such as INF-xcex3, TNF-xcex1 and LI-1xcex2.
Regulation of xcex14xcex21 mediated cell adhesion is important in numerous physiological processes, including T-cell proliferation, B-cell localisation to germinal centres, and adhesion of activated T-cells and eosinophils to endothelial cells. Evidence for the involvement of VLA-4/VCAM-1 interaction in various disease processes such as melanoma cell division in metastasis, T-cell infiltration of synovial membranes in rheumatoid arthritis, autoimmune diabetes, collitis and leukocyte penetration of the blood-brain barrier in experimental autoimmune encephalomyelitis, atherosclerosis, peripheral vascular disease, cardiovascular disease and multiple sclerosis, has been accumulated by investigating the role of the peptide CS-1 (the variable region of fibronectin to which xcex14xcex21 binds via the sequence Leu-Asp-Val) and antibodies specific for VLA-4 or VCAM-1 in various in vitro and in vivo experimental models of inflammation. For example, in a Streptococcal cell wall-induced experimental model of arthritis in rats, intravenous administration of CS-1 at the initiation of arthritis suppresses both acute and chronic inflammation (S. M. Wahl et al., J.Clin.lnvest., 1994, 94, pages 655-662). In the oxazalone-sensitised model of inflammation (contact hypersensitivity response) in mice, intravenous administration of anti-xcex14 specific monoclonal antibodies significantly inhibited (50-60% reduction in the ear swelling response) the efferent response (P. L. Chisholm et al. J.lmmunol., 1993, 23, pages 682-688).
We have now found a novel group of substituted anilides which have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (xcex14xcex21).
Thus, in one aspect, the present invention is directed to compounds of general formula (I): 
wherein:
R1 is hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy;
X1, X2 and X6 independently represent N or CR10; and
one of X3, X4 and X5 represents CR11 and the others independently represents N or CR10 [where R10 is hydrogen, amino, halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, nitro or trifluoromethyl; and R11 represents a group xe2x80x94L1xe2x80x94Ar1xe2x80x94L2xe2x80x94Y in which:
L1 represents a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage, where R2 is a straight or branched C1-6alkylene chain, a straight or branched C2-6alkenylene chain or a straight or branched C2-6alkynylene chain, and R3 is a direct bond, cycloalkylene, heterocycloalkylene, arylene, heteroaryldiyl, xe2x80x94C(xe2x95x90Z)xe2x80x94NR4xe2x80x94, xe2x80x94NR4xe2x80x94C(xe2x95x90Z)xe2x80x94, xe2x80x94Z1xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90NOR4)xe2x80x94, xe2x80x94NR4xe2x80x94C(xe2x95x90Z)xe2x80x94NR4xe2x80x94, xe2x80x94SO2xe2x80x94NR4xe2x80x94, xe2x80x94NR4xe2x80x94SO2xe2x80x94, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NR4xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94NR4xe2x80x94 (where R4 is a hydrogen atom or a lower alkyl group; Z is O or S; Z1 is O, S(O)n or NR4 and n is zero or an integer 1 or 2); but excluding compounds where an oxygen, nitrogen or sulphur atom in R3 is attached directly to a carbon carbon multiple bond in R2;
Ar1 is arylene or heteroaryldiyl;
L2 represents:
(i) a direct bond;
(ii) an alkylene, alkenylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene linkage each optionally substituted by (a) an acidic functional group (or corresponding protected derivative), R5, xe2x80x94ZH, xe2x80x94ZR5, xe2x80x94C(xe2x95x90O)xe2x80x94R5, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94R13, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94OR13, xe2x80x94N(R12)xe2x80x94SO2xe2x80x94R13, xe2x80x94NY1Y2, or xe2x80x94[C(xe2x95x90O)xe2x80x94N(R6)xe2x80x94C(R4)(R7)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2, or by (b) alkyl substituted by an acidic functional group (or corresponding protected derivative), or by xe2x80x94ZH, xe2x80x94ZR5, xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2 or xe2x80x94NY1Y2;
(iii) a xe2x80x94[C(xe2x95x90O)xe2x80x94N(R6)xe2x80x94C(R4)(R7)]pxe2x80x94 linkage;
(iv) a xe2x80x94Z2xe2x80x94R9xe2x80x94 linkage;
(v) a xe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94 linkage;
(vi) a xe2x80x94R9xe2x80x94Z2xe2x80x94R9xe2x80x94 linkage; or
(vii) a xe2x80x94C(R4)(R8)xe2x80x94[C(xe2x95x90O)xe2x80x94N(R6)xe2x80x94C(R4)(R7)]pxe2x80x94 linkage;
xe2x80x83{in which
R5 is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl, or heterocycloalkylalkyl;
R6 is hydrogen, R5 or alkyl substituted with alkoxy, cycloalkyl, hydroxy, mercapto, alkylthio or xe2x80x94NY1Y2;
R7 and R8 are each independently selected from hydrogen or a group consisting amino acid side chains and corresponding protected derivatives, an acidic functional group (or corresponding protected derivative), R5, xe2x80x94ZR5, xe2x80x94C(xe2x95x90O)xe2x80x94R5, or xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2, or alkyl substituted by an acidic functional group (or corresponding protected derivative)or by R5, xe2x80x94ZR5, xe2x80x94NY1Y2, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94R5, xe2x80x94C(xe2x95x90O)xe2x80x94R2xe2x80x94NH2, xe2x80x94C(xe2x95x90O)xe2x80x94Ar1xe2x80x94NH2, xe2x80x94C(xe2x95x90O)xe2x80x94R2xe2x80x94CO2H, or xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2;
or R6 and R7 or R6 and R8 together with the atoms to which they attached form a 3- to 6-membered heterocycloalkyl ring;
R9 is C1-6alkylene, optionally substituted by R5;
R12 is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
R13 is alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, or alkyl substituted by aryl, an acidic functional group (or corresponding protected derivative), cycloalkyl, heteroaryl, heterocycloalkyl, xe2x80x94ZH, xe2x80x94ZR5, xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2 or xe2x80x94NY1Y2;
Y1 and Y2 are independently hydrogen, alkenyl, alkyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkyl substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, xe2x80x94NY1Y2, or one or more xe2x80x94CO2R12 or xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2 groups; or the group xe2x80x94NY1Y2 may form a 5- to 7-membered cyclic amine which (i) may be optionally substituted with one or more substituents selected from alkoxy, carboxamido, carboxy, hydroxy, oxo (or a 5-, 6- or 7-membered cyclic acetal derivative thereof), R13; (ii) may also contain a further heteroatom selected from O, S, SO2, or NY3 [where Y3 is hydrogen, alkyl, aryl, arylalkyl, xe2x80x94C(xe2x95x90O)xe2x80x94R14, xe2x80x94C(xe2x95x90O)xe2x80x94OR14 or xe2x80x94SO2R14 (in which R14 is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl)]; and (iii) may also be fused to additional aryl, heteroaryl, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system;
Z2 is O S(O)n, NR4, SONR4, C(xe2x95x90O)NR4 or C(xe2x95x90O); and
p is zero or an integer 1 to 4}; and
Y is carboxy (or an acid bioisostere) or xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2];
and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs; excluding the compounds (2-{2-[4-(3-(2-methylphenyl)ureido)-phenyl]-acetylamino}-thiazol-4-yl)-acetic acid, 2-phenylacetylamino-3-{4-[4-(3-(2-methylphenyl)ureido)-benzyloxy]-phenyl}-propionic acid, 2-phenylacetylamino-3-(4{2-[4-(3-(2-methylphenyl)ureido)-phenyl]-ethoxy}-phenyl)-propionic acid, 2-benzylsulphonylamino-3-{4-[4-(3-(2-methylphenyl)ureido)-benzyloxy]-phenyl}-propionic acid, (butane-1-sulphonylamino)-{2-[4-(3-(2-methylphenyl)-ureido)-benzyl]-benzofuran-6-yl}-acetic acid, 3-(benzylaminocarbonyl)-(4{2-[4-(3-(2-methylphenyl)ureido)-phenyl]-ethoxy}-benzyl)-propionic acid and 2-benzyloxycarbonylamino-3-(5-{3-[4-(3-(2-methylphenyl)ureido)-phenyl]-propyl}-thiophene-2-yl)-propionic acid; and with the proviso that L1 cannot represent C1-6alkylene-C(xe2x95x90O)xe2x80x94NHxe2x80x94 or C1-6alkylene when Ar1 represents optionally substituted phenylene, Y represents xe2x80x94CO2H, xe2x80x94SO3H, xe2x80x94PO4H2 or tetrazole, and L2 represents (i) a direct bond, (ii) an alkylene or alkenylene linkage each optionally substituted by (a) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl, or by (b) alkyl substituted by alkoxy, hydroxy, arylalkyoxy, heteroarylalkyloxy, alkylthio, carboxy, alkoxycarbonyl, or xe2x80x94C(xe2x95x90O)xe2x80x94NH2, (iii) a xe2x80x94[C(xe2x95x90O)xe2x80x94N(R6)xe2x80x94C(R4)(R7)]pxe2x80x94 linkage in which R4 is hydrogen or lower alkyl, R6 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl or alkyl substituted by alkoxy, hydroxy or alkylthio, R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl or alkyl substituted by alkenyl, alkynyl, alkoxy, hydroxy, arylalkyloxy, heteroarylalkyloxy, alkylthio, carboxy, alkoxycarbonyl or carboxamide, and p is one, (iv) a xe2x80x94Z2xe2x80x94R9xe2x80x94 linkage in which Z2 is O, S, NR4, SO2NR4 or C(xe2x95x90O)NR4 and R9 is C1-4alkylene, optionally substituted by alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl, or (v) a xe2x80x94CH2xe2x80x94Z2xe2x80x94R9xe2x80x94 linkage in which Z2 is O, NR4 or C(xe2x95x90O)NR4 and R9 is C1-4alkylene, optionally substituted by alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl.
In the present specification, the term xe2x80x9ccompounds of the inventionxe2x80x9d, and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cPatientxe2x80x9d includes both human and other mammals.
xe2x80x9cAcid bioisosterexe2x80x9d means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986,21,p283 xe2x80x9cBioisosterism In Drug Designxe2x80x9d; Yun, Hwahak Sekye, 1993,33,p576-579 xe2x80x9cApplication Of Bioisosterism To New Drug Designxe2x80x9d; Zhao, Huaxue Tongbao, 1995,p34-38 xe2x80x9cBioisosteric Replacement And Development Of Lead Compounds In Drug Designxe2x80x9d; Graham, Theochem, 1995,343,p105-109 xe2x80x9cTheoretical Studies Applied To Drug Design:ab initio Electronic Distributions In Bioisosteresxe2x80x9d). Examples of suitable acid bioisosteres include: xe2x80x94C(xe2x95x90O)xe2x80x94NHOH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2OH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2SH, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, heteroarylsulphonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydoxy-1-methylpyrazolyl.
xe2x80x9cAcidic functional groupxe2x80x9d means a group with an acidic hydrogen within it. The xe2x80x9ccorresponding protected derivativesxe2x80x9d are those where the acidic hydrogen atom has been replaced with a suitable protecting group. For suitable protecting groups see T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991. Exemplary acidic functional groups include carboxyl (and acid bioisosteres), hydroxy, mercapto and imidazole. Exemplary protected derivatives include esters of carboxy groups, ethers of hydroxy groups, thioethers of mercapto groups and N-benzyl derivatives of imidazoles.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94COxe2x80x94 or alkyl-COxe2x80x94 group in which the alkyl group is as described herein.
xe2x80x9cAcylaminoxe2x80x9d is an acyl-NHxe2x80x94 group wherein acyl is as defined herein.
xe2x80x9cAlkenylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. xe2x80x9cBranchedxe2x80x9d, as used herein and throughout the text, means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain. xe2x80x9cLower alkenylxe2x80x9d means about 2 to about 4 carbon atoms in the chain which may be straight or branched. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
xe2x80x9cAlkenylenexe2x80x9d means an aliphatic bivalent radical derived from a straight or branched alkenyl group, in which the alkenyl group is as described herein. Exemplary alkenylene radicals include vinylene and propylene.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-Oxe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
xe2x80x9cAlkoxyalkoxyxe2x80x9d means an alkyl-O-alkyl-Oxe2x80x94 group wherein the alkyl groups independently are as defined above. Examples of alkoxyalkoxyl include methoxymethoxy, methoxyethoxy, ethoxyethoxy and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an alkyl-Oxe2x80x94COxe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
xe2x80x9cAlkylxe2x80x9d means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain optionally substituted by alkoxy or by one or more halogen atoms. Particular alkyl groups have from 1 to about 6 carbon atoms. xe2x80x9cLower alkylxe2x80x9d as a group or part of a lower alkoxy, lower alkylthio, lower alkylsulphinyl or lower alkylsulphonyl group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 4 carbon atoms in the chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.
xe2x80x9cAlkylenexe2x80x9d means an aliphatic bivalent radical derived from a straight or branched alkyl group, in which the alkyl group is as described herein. Exemplary alkylene radicals include methylene, ethylene and trimethylene.
xe2x80x9cAlkylenedioxyxe2x80x9d means an xe2x80x94O-alkylene-Oxe2x80x94 group in which alkylene is as defined above. Exemplary alkylenedioxy groups include methylenedioxy and ethylenedioxy.
xe2x80x9cAlkylsulphinylxe2x80x9d means an alkyl-SOxe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulphinyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylsulphonylxe2x80x9d means an alkyl-SO2xe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulphonyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylsulphonylcarbamoylxe2x80x9d means an alkyl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulphonylcarbamoyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.
xe2x80x9cAlkynylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.
xe2x80x9cAlkynylenexe2x80x9d means an aliphatic bivalent radical derived from a straight or branched alkynyl group, in which the alkynyl group is as described herein. Exemplary alkynylene radicals include ethynylene and propynylene.
xe2x80x9cAmino acid side chainsxe2x80x9d means the substituent found on the carbon between the amino and carboxy groups in xcex1-amino acids. For examples of xe2x80x9ccorresponding protected derivativesxe2x80x9d of amino acid side chains, see T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991.
xe2x80x9cAroylxe2x80x9d means an aryl-COxe2x80x94 group in which the aryl group is as described herein. Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
xe2x80x9cAroylaminoxe2x80x9d is an aroyl-NHxe2x80x94 group wherein aroyl is as previously defined.
xe2x80x9cArylxe2x80x9d as a group or part of a group denotes: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic moiety in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring. Aryl groups may be substituted with one or more aryl group substituents which may be the same or different, where xe2x80x9caryl group substituentxe2x80x9d includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulphinyl, alkylsulphonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulphinyl, arylsulphonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, Y4Y5Nxe2x80x94, Y4Y5NCOxe2x80x94, Y4Y5NSO2xe2x80x94 (where Y4 and Y5 are independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl), Y4Y5Nxe2x80x94C2-6alkylene-Z3xe2x80x94 {where Z3 is O, NR6 or S(O)n}, alkylC(xe2x95x90O)xe2x80x94Y4Nxe2x80x94, alkylSO2xe2x80x94Y4Nxe2x80x94 or alkyl optionally substituted with aryl, heteroaryl, hydroxy, or Y4Y5Nxe2x80x94. When L2 contains an optionally substituted aryl group, this may particularly represent optionally substituted phenyl.
xe2x80x9cArylalkenylxe2x80x9d means an aryl-alkenyl group in which the aryl and alkenyl are as previously described. Preferred arylalkenyls contain a lower alkenyl moiety. Exemplary arylalkenyl groups include styryl and phenylallyl.
xe2x80x9cArylalkylxe2x80x9d means an aryl-alkyl-group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C1-4alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
xe2x80x9cArylalkyloxyxe2x80x9d means an arylalkyl-Oxe2x80x94 group in which the arylalkyl groups is as previously described. Exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
xe2x80x9cArylalkyloxycarbonylxe2x80x9d means an arylalkyl-Oxe2x80x94COxe2x80x94 group in which the arylalkyl groups is as previously described. An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.
xe2x80x9cArylalkylthioxe2x80x9d means an arylalkyl-Sxe2x80x94 group in which the arylalkyl group is as previously described. An exemplary arylalkylthio group is benzylthio.
xe2x80x9cArylalkynylxe2x80x9d means an aryl-alkynyl-group in which the aryl and alkynyl are as previously described. Exemplary arylalkynyl groups include phenylethynyl and 3-phenylbut-2-ynyl.
xe2x80x9cArylenexe2x80x9d means an optionally substituted bivalent radical derived from an aryl group. Exemplary arylene groups include optionally substituted phenylene, naphthylene and indanylene. When Ar1 is arylene this may particularly represent an optionally substituted phenylene. Suitable substituents include one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above, particularly halogen, methyl or methoxy.
xe2x80x9cAryloxyxe2x80x9d means an aryl-Oxe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxy groups include optionally substituted phenoxy and naphthoxy.
xe2x80x9cAryloxycarbonylxe2x80x9d means an aryl-Oxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
xe2x80x9cArylsulphinylxe2x80x9d means an aryl-SOxe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylsulphonylxe2x80x9d means an aryl-SO2xe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylsulphonylcarbamoylxe2x80x9d means an aryl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylthioxe2x80x9d means an aryl-Sxe2x80x94 group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio.
xe2x80x9cAzaheteroarylxe2x80x9d means an aromatic carbocyclic moiety of about 5 to about 10 ring members in which one of the ring members is nitrogen and the other ring members are chosen from carbon, oxygen, sulphur, or nitrogen. Examples of azaheteroaryl groups include pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, imidazolyl, and benzimidazolyl.
xe2x80x9cCycloalkenylxe2x80x9d means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
xe2x80x9cCycloalkenylalkylxe2x80x9d means a cycloalkenyl-alkyl-group in which the cycloalkenyl and alkyl moieties are as previously described. Exemplary cycloalkenylalkyl groups include cyclopentenylmethyl, cyclohexenylmethyl or cycloheptenylmethyl.
xe2x80x9cCycloalkenylenexe2x80x9d means a bivalent radical derived from an unsaturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing a hydrogen atom from each of two different carbon atoms of the ring. Exemplary cycloalkenylene radicals include cyclopentenylene and cyclohexenylene.
xe2x80x9cCycloalkylxe2x80x9d means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms optionally substituted by oxo. Exemplary monocyclic cycloalkyl rings include C3-8cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
xe2x80x9cCycloalkylalkylxe2x80x9d means a cycloalkyl-alkyl-group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
xe2x80x9cCycloalkylenexe2x80x9d means a bivalent radical derived from a saturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing a hydrogen atom from each of two different carbon atoms of the ring. Exemplary cycloalkenylene radicals include cyclopentylene and cyclohexylene.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro.
xe2x80x9cHeteroaroylxe2x80x9d means a heteroaryl-C(xe2x95x90O)xe2x80x94 group in which the heteroaryl group is as described herein. Exemplary groups include pyridylcarbonyl.
xe2x80x9cHeteroaroylaminoxe2x80x9d means a heteroaroyl-NHxe2x80x94 group in which the heteroaryl moiety are as previously described.
xe2x80x9cHeteroarylxe2x80x9d as a group or part of a group denotes: (i) an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur (examples of such groups include benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally substituted by one or more aryl group substituents as defined above); (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which a heteroaryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure (examples of such groups include pyrindanyl groups). Optional substituents include one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above. When L2 contains an optionally substituted heteroaryl group this may particularly represent an optionally substituted xe2x80x9cazaheteroarylxe2x80x9d group.
xe2x80x9cHeteroarylalkenylxe2x80x9d means a heteroaryl-alkenyl-group in which the heteroaryl and alkenyl moieties are as previously described. Preferred heteroarylalkenyl groups contain a lower alkenyl moiety. Exemplary heteroarylalkenyl groups include pyridylethenyl and pyridylallyl.
xe2x80x9cHeteroarylalkylxe2x80x9d means a heteroaryl-alkyl-group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C1-4alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
xe2x80x9cHeteroarylalkyloxyxe2x80x9d means an heteroarylalkyl-Oxe2x80x94 group in which the heteroarylalkyl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridylmethoxy.
xe2x80x9cHeteroarylalkynylxe2x80x9d means a heteroaryl-alkynyl-group in which the heteroaryl and alkynyl moieties are as previously described. Exemplary heteroarylalkenyl groups include pyridylethynyl and 3-pyridylbut-2-ynyl.
xe2x80x9cHeteroaryldiylxe2x80x9d means a bivalent radical derived from an aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur, and optionally substituted by one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above. When Ar1 is a heteroaryldiyl radical this may particularly represent an optionally substituted pyridindiyl.
xe2x80x9cHeteroaryloxyxe2x80x9d means an heteroaryl-Oxe2x80x94 group in which the heteroaryl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridyloxy.
xe2x80x9cHeteroarylsulphonylcarbamoylxe2x80x9d means a heteroaryl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the heteroaryl group is as previously described.
xe2x80x9cHeterocycloalkylxe2x80x9d means: (i) a cycloalkyl group of about 3 to 7 ring members which contains one or more heteroatoms selected from O, S or NY6 (where Y6 is hydrogen, alkyl, arylalkyl, and aryl); (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which an aryl (or heteroaryl ring) and a heterocycloalkyl group are fused together to form a cyclic structure (examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups,
xe2x80x9cHeterocycloalkylalkylxe2x80x9d means a heterocycloalkyl-alkyl-group in which the heterocycloalkyl and alkyl moieties are as previously described.
xe2x80x9cHeterocycloalkylenexe2x80x9d means a bivalent radical derived from a saturated monocyclic hydrocarbon of about 5 to about 7 atoms, which contains one or more heteroatoms selected from O, S or NY6 (where Y6 is hydrogen, alkyl, arylalkyl, and aryl) and is optionally substituted by oxo, by removing a hydrogen atom from each of two different carbon atoms of the ring, or when NY6 is NH by removing a hydrogen atom from one carbon atom of the ring and a hydrogen atom from the NH, or when the ring contains two NY6 heteroatoms and NY6 is NH by removing a hydrogen atom from both nitrogen atoms.
xe2x80x9cY4Y5Nxe2x80x94xe2x80x9d means a substituted or unsubstituted amino group, wherein Y4 and Y5 are as previously described. Exemplary groups include amino (H2Nxe2x80x94), methylamino, ethylmethylamino, dimethylamino and diethylamino.
xe2x80x9cY4Y5NCOxe2x80x94xe2x80x9d means a substituted or unsubstituted carbamoyl group, wherein Y4 and Y5 are as previously described. Exemplary groups are carbamoyl (H2NCOxe2x80x94) and dimethylcarbamoyl (Me2NCOxe2x80x94).
xe2x80x9cY4Y5NSO2xe2x80x94xe2x80x9d means a substituted or unsubstituted sulphamoyl group, wherein Y4 and Y5 are as previously described. Exemplary groups are sulphamoyl (H2NSO2xe2x80x94) and dimethylsulphamoyl (Me2NSO2xe2x80x94).
xe2x80x9cProdrugxe2x80x9d means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides thereof. For example an ester of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
Suitable esters of compounds of formula (I) containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-xcex2-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
An especially useful class of esters of compounds of formula (I) containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32, page 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
Where the compound of the invention contains a carboxy group, or a sufficiently acidic bioisostere, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
Some of the compounds of the present invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
Acid addition salts are a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g. hydrochlorides and hydrobromides, sulphates, phosphates, nitrates, sulphamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
With reference to formula (I) above, the following are particular and preferred groupings:
R1 may particularly represent hydrogen, especially when X1 represents Cxe2x80x94R10 where R10 is lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl or lower alkylsulphonyl.
R1 may also particularly represent halogen, especially fluoro and chloro.
R1 may also particularly represent lower alkyl (e.g. methyl), especially when X1 represents N.
R1 may also particularly represent lower alkoxy (e.g. methoxy), especially when X1 represents N.
X1 may particularly represent CR10, especially where R10 is lower alkyl or lower alkoxy (e.g. methyl or methoxy).
X1 may also particularly represent N.
X2 may particularly represent CR10, especially where R10 is lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), lower alkylthio (e.g. methylthio), lower alkylsulphinyl (e.g. methylsulphinyl) or lower alkylsulphonyl (e.g. methylsulphonyl).
X3 may particularly represent CH.
X3 may also particularly represent N.
X6 may particularly represent CR10 and is preferably CH.
One of X4 and X5 may particularly represent CR11 and the other represents CR10, especially CH.
Within R11 the moiety L1 may particularly represent a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage where R2 represents a straight or branched C1-6alkylene chain, especially a straight or branched C1-4alkylene chain, and R3 represents (a) xe2x80x94C(xe2x95x90Z)xe2x80x94NR4xe2x80x94, preferably xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, or (b) xe2x80x94Z1xe2x80x94, preferably xe2x80x94Oxe2x80x94.
Within R11 the moiety Ar1 may particularly represent (a) an optionally substituted arylene, such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene or (b) an optionally substituted heteroaryldiyl, such as optionally substituted pyridindiyl, preferably a p-pyridindiyl, more preferably a pyridin-2,5-diyl. Preferred optional substituents include C1-4alkyl, especially methyl, and C1-4alkoxy, especially methoxy.
Within R11 the moiety L2 may particularly represent (a) a direct bond (b) an optionally substituted alkylene linkage, especially optionally substituted ethylene (c) an unsubstituted alkenylene linkage, especially vinylene or (d) a xe2x80x94Z2xe2x80x94R9xe2x80x94 linkage, such as xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94S(O)nxe2x80x94CH2xe2x80x94, xe2x80x94S(O)nxe2x80x94CH2xe2x80x94CH2xe2x80x94, or especially xe2x80x94NHxe2x80x94CH2xe2x80x94. Preferred optional substituents within (b) include lower alkyl (e.g. methyl), aryl, heteroaryl, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94R13, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94OR13, xe2x80x94N(R12)xe2x80x94SO2xe2x80x94R13, xe2x80x94NY1Y2 and xe2x80x94[C(xe2x95x90O)xe2x80x94N(R6)xe2x80x94C(R4)(R7)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2. L2 is preferably a group 
where R4 is hydrogen or lower alkyl (e.g. methyl) and R15 represents lower alkyl (e.g. methyl), or where R4 is hydrogen and R15 represents aryl, heteroaryl, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94R13, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94OR13, xe2x80x94N(R12)xe2x80x94SO2xe2x80x94R13, xe2x80x94NY1Y2 or xe2x80x94[C(xe2x95x90O)xe2x80x94N(R6)xe2x80x94C(R4)(R7)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2. L2 is more preferably a group 
particularly 
where R15 represents xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94R13, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94OR13, xe2x80x94N(R12)xe2x80x94SO2xe2x80x94R13 or xe2x80x94NY1Y2.
Within R11 the moiety Y may particularly represent carboxy or an acid bioisostere.
It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.
A particular group of compounds of the invention are compounds of formula (Ia): 
in which R1, R2, L2, X1, X2, X3 and Y are as hereinbefore defined, Ar1 is arylene and xe2x80x94R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94Ar1xe2x80x94L2xe2x80x94Y is attached at the ring 3 or 4 position, and their prodrugs and pharmaceutically acceptable salts, and solvates (e.g. hydrates) of compounds of formula (Ia) and their prodrugs.
Compounds of formula (Ia) in which R1 represents hydrogen are preferred.
Compounds of formula (Ia) in which R2 represents a straight or branched C1-6alkylene chain, especially a straight or branched C1-4alkylene chain, more especially methylene, are preferred.
Compounds of formula (Ia) in which Ar1 represents an optionally substituted arylene, especially optionally substituted m- or p-phenylene, more especially optionally substituted p-phenylene, are preferred. Preferred substituents for Ar1 include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy.
Compounds of formula (Ia) in which L2 represents an optionally substituted alkylene linkage, especially ethylene or substituted ethylene, are preferred. Preferred optional substituents include lower alkyl (e.g. methyl), aryl, heteroaryl, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94R13, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94OR13, xe2x80x94N(R12)xe2x80x94SO2xe2x80x94R13, xe2x80x94NY1Y2 or xe2x80x94[C(xe2x95x90O)xe2x80x94N(R6)xe2x80x94C(R4)(R7)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2. Compounds of formula (Ia) in which L2 is a 
linkage, where R4 is hydrogen or lower alkyl (e.g. methyl) and R15 represents lower alkyl (e.g. methyl), or where R4 is hydrogen and R15 represents aryl, heteroaryl, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94R13, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94OR13, xe2x80x94N(R12)xe2x80x94SO2xe2x80x94R13, xe2x80x94NY1Y2 and xe2x80x94[C(xe2x95x90O)xe2x80x94N(R6)xe2x80x94C(R4)(R7)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2 are particularly preferred. Compounds of formula (Ia) in which L2 represents a 
linkage, particularly 
where R15 represents xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94R13, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94OR13, xe2x80x94N(R12)xe2x80x94SO2xe2x80x94R13 or xe2x80x94NY1Y2 are especially preferred.
Compounds of formula (Ia) in which X1 represents CR10, especially where R10 is lower alkyl or lower alkoxy(e.g. methyl or methoxy), are preferred.
Compounds of formula (Ia) in which X2 represents CR10, especially where R10 is lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), lower alkylthio (e.g. methylthio), lower alkylsulphinyl (e.g. methylsulphinyl) or lower alkylsulphonyl (e.g. methylsulphonyl), are also preferred.
Compounds of formula (Ia) in which X3 represents CH are also preferred.
Compounds of formula (Ia) in which Y represents carboxy are preferred.
The group xe2x80x94R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94Ar1xe2x80x94L2xe2x80x94Y may preferably be attached at the ring 4 position.
A preferred group of compounds of the invention are compounds of formula (Ia) in which: R1 is hydrogen; R2 is a straight or branched C1-4alkylene chain, (especially methylene), Ar1 is an optionally substituted arylene [especially p-phenylene, and methyl(or methoxy) substituted p-phenylene]; L2 is a substituted alkylene linkage [especially 
where R15 represents xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94R13, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94OR13, xe2x80x94N(R12)xe2x80x94SO2xe2x80x94R13 or xe2x80x94NY1Y2]; X1 and X2 represent CR10 (especially where R10 is methyl, methoxy, methylthio, methylsulphinyl or methylsuphonyl); X3 represents CH; Y represents carboxy; and the group xe2x80x94R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94Ar1xe2x80x94L2xe2x80x94Y is attached at the ring 4 position; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Compounds of formula (Ia) in which R15 represents xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94R13, especially where R12 is hydrogen or lower alkyl (e.g. methyl) and R13 is lower alkyl (e.g. methyl), aryl (e.g. optionally substituted phenyl), heteroaryl (e.g. optionally substituted pyridyl, optionally substituted thienyl, optionally substituted isoxazolyl, optionally substituted pyridazyl), heterocycloalkyl (e.g. tetrahydropyran-4-yl), alkyl substituted by carboxy (e.g. xe2x80x94CH2xe2x80x94CH2xe2x80x94CO2H and xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CO2H), alkyl substituted by xe2x80x94NY1Y2 (e.g. aminomethyl and morpholin-1-ylmethyl) or alkyl substituted by alkoxyalkoxy (e.g. xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH3) are preferred.
Compounds of formula (Ia) in which R15 represents xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94OR13, especially where R12 is hydrogen or lower alkyl (e.g. methyl) and R13 is lower alkyl (e.g. ethyl) or alkyl substituted by aryl (e.g. benzyl), are also preferred.
Compounds of formula (Ia) in which R15 represents xe2x80x94N(R12)xe2x80x94SO2xe2x80x94R13, especially where R12 is hydrogen or lower alkyl (e.g. methyl) and R13 is lower alkyl (e.g. methyl), aryl [e.g. optionally substituted phenyl or optionally substituted naphthyl (especially dimethylaminonaphth-1-yl)]), heteroaryl (e.g. optionally substituted pyridyl or optionally substituted imidazolyl), are also preferred.
Compounds of formula (Ia) in which R15 represents xe2x80x94NY1Y2, especially where Y1 and Y2 represent hydrogen are also preferred.
Compounds of formula (Ia) in which R15 represents xe2x80x94NY1Y2, especially where Y1 is hydrogen and Y2 is or lower alkyl (e.g. propyl), or alkyl substituted by aryl (e.g. xe2x80x94CH2-Ph, xe2x80x94CH(CH3)-Ph or xe2x80x94CH2xe2x80x94CH2-Ph), are also preferred.
Particularly preferred compounds of formula (Ia) are those in which R15 is xe2x80x94NH2, 
A further particular group of compounds of the invention are compounds of formula (Ib): 
in which R1, R2, L2, X1, X2, X3 and Y are as hereinbefore defined, Ar1 is heteroaryldiyl and xe2x80x94R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94Ar1xe2x80x94L2xe2x80x94Y is attached at the ring 3 or 4 position, and their prodrugs and pharmaceutically acceptable salts, and solvates (e.g. hydrates) of compounds of formula (Ib) and their prodrugs.
Compounds of formula (Ib) in which R1 represents hydrogen are preferred.
Compounds of formula (Ib) in which R2 represents a straight or branched C1-6alkylene chain, especially a straight or branched C1-4alkylene chain, more especially methylene, are preferred.
Compounds of formula (Ib) in which Ar1 represents an optionally substituted heteroaryldiyl, especially optionally substituted pyridindiyl, more especially optionally substituted p-pyridindiyl, preferably pyridin-2,5-diyl, are also preferred. Preferred substituents include C1-4alkyl and C1-4alkoxy, especially methyl and methoxy.
Compounds of formula (Ib) in which L2 represents an optionally substituted alkylene linkage, especially ethylene or substituted ethylene, are preferred. Preferred optional substituents include lower alkyl (e.g. methyl), aryl, heteroaryl, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94R13, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94OR13, xe2x80x94N(R12)xe2x80x94SO2xe2x80x94R13, xe2x80x94NY1Y2 or xe2x80x94[C(xe2x95x90O)xe2x80x94N(R6)xe2x80x94C(R4)(R7)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2. Compounds of formula (Ib) in which L2 is a 
linkage, where R4 is hydrogen or lower alkyl (e.g. methyl) and R15 represents lower alkyl (e.g. methyl), or where R4 is hydrogen and R15 represents aryl, heteroaryl, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94R13, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94OR13, xe2x80x94N(R12)xe2x80x94SO2xe2x80x94R13, xe2x80x94NY1Y2 and xe2x80x94[C(xe2x95x90O)xe2x80x94N(R6)xe2x80x94C(R4)(R7)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2 are particularly preferred. Compounds of formula (Ib) in which L2 represents a 
linkage, particularly 
where R15 represents xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94R13, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94OR13, xe2x80x94N(R12)xe2x80x94SO2xe2x80x94R13 or xe2x80x94NY1Y2 are especially preferred.
Compounds of formula (Ib) in which X1 represents CR10, especially where R10 is lower alkyl or lower alkoxy(e.g. methyl or methoxy), are preferred.
Compounds of formula (Ib) in which X2 represents CR10, especially where R10 is lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), lower alkylthio (e.g. methylthio), lower alkylsulphinyl (e.g. methylsulphinyl) or lower alkylsulphonyl (e.g. methylsulphonyl), are also preferred.
Compounds of formula (Ib) in which X3 represents CH are also preferred.
Compounds of formula (Ib) in which Y represents carboxy are preferred.
The group xe2x80x94R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94Ar1xe2x80x94L2xe2x80x94Y may preferably be attached at the ring 4 position.
A preferred group of compounds of the invention are compounds of formula (Ib) in which: R1 is hydrogen; R2 is a straight or branched C1-4alkylene chain, (especially methylene), Ar1 is an optionally substituted heteroaryldiyl, (especially pyridin-2,5-diyl); L2 is an optionally substituted alkylene linkage (especially an ethylene, or a 
linkage, particularly 
where R15 represents methyl, aryl, heteroaryl, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94R13, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)-OR13, xe2x80x94N(R12)xe2x80x94SO2xe2x80x94R13, xe2x80x94NY1Y2 and xe2x80x94[C(xe2x95x90O)xe2x80x94N(R6)xe2x80x94C(R4)(R7)]pxe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2 [especially xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94R13, xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94OR13, xe2x80x94N(R12)xe2x80x94SO2xe2x80x94R13 or xe2x80x94NY1Y2]; X1 and X2 represent CR10 (especially where R10 is methyl, methoxy, methylthio, methylsulphinyl or methylsuphonyl); X3 represents CH; Y represents carboxy; and the group xe2x80x94R2xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94Ar1xe2x80x94L2xe2x80x94Y is attached at the ring 4 position; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Compounds of formula (Ib) in which R15 represents xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94R13, especially where R12 is hydrogen or lower alkyl (e.g. methyl) and R13 is lower alkyl (e.g. methyl), aryl (e.g. optionally substituted phenyl), heteroaryl (e.g. optionally substituted pyridyl, optionally substituted thienyl, optionally substituted isoxazolyl, optionally substituted pyridazyl), heterocycloalkyl (e.g. tetrahydropyran-4-yl), alkyl substituted by carboxy (e.g. xe2x80x94CH2xe2x80x94CH2xe2x80x94CO2H and xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CO2H), alkyl substituted by xe2x80x94NY1Y2 (e.g. aminomethyl and morpholin-1-ylmethyl) or alkyl substituted by alkoxyalkoxy (e.g. xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH3) are preferred.
Compounds of formula (Ib) in which R15 represents xe2x80x94N(R12)xe2x80x94C(xe2x95x90O)xe2x80x94OR13, especially where R12 is hydrogen or lower alkyl (e.g. methyl) and R13 is lower alkyl (e.g. ethyl) or alkyl substituted by aryl (e.g. benzyl), are also preferred.
Compounds of formula (Ib) in which R15 represents xe2x80x94N(R12)xe2x80x94SO2xe2x80x94R13, especially where R12 is hydrogen or lower alkyl (e.g. methyl) and R13 is lower alkyl (e.g. methyl), aryl [e.g. optionally substituted phenyl or optionally substituted naphthyl (especially dimethylaminonaphth-1-yl)]), heteroaryl (e.g. optionally substituted pyridyl or optionally substituted imidazolyl), are also preferred.
Compounds of formula (Ib) in which R15 represents xe2x80x94NY1Y2, especially where Y1 and Y2 represent hydrogen are also preferred.
Compounds of formula (Ib) in which R15 represents xe2x80x94NY1Y2, especially where Y1 is hydrogen and Y2 is or lower alkyl (e.g. propyl), or alkyl substituted by aryl (e.g. xe2x80x94CH2-Ph or xe2x80x94CH2xe2x80x94CH2-Ph), are also preferred.
Compounds of formula (Ib) in which R15 represents xe2x80x94NY1Y2, especially where both Y1 and Y2 represent alkyl substituted by aryl (e.g. xe2x80x94CH2-Ph or xe2x80x94CH(CH3)-Ph), are also preferred.
Particularly preferred compounds of formula (Ib) are those in which R15 is xe2x80x94NH2, 
Particular compounds of the invention are selected from the following:
(5-{4-[3-(2-methylphenyl)ureido]-phenylacetylamino}pyrid-2-yl)-thioacetic acid;
3-(5-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}pyrid-2-yl)-propanoic acid;
3-(5-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}pyrid-2-yl)-2-methyl-propanoic acid;
3-(6-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}pyrid-3-yl)-propanoic acid;
3-acetylamino-3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino)}-pyridin-3-yl)-propionic acid;
3-(3,4-dimethoxy-benzoylamino)-3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino})-pyridin-3-yl)-propionic acid;
N-[2-carboxy-1-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-ethyl]-terephthalamic acid;
3-benzoylamino-3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-3-[(tetrahydro-pyran-4-carbonyl)-amino]-propionic acid;
3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-[(pyridazine-3-carbonyl)-amino]-propionic acid;
3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-3-[(thiophene-2-carbonyl)-amino]-propionic acid;
N-[2-carboxy-1-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-ethyl]-succinamic acid;
4-[2-carboxy-1-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-ethylcarbamoyl]-butyric acid;
3-(2-amino-acetylamino)-3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-3-(2-morpholin-4-yl-acetylamino)-propionic acid;
3-[2-(2-methoxy-ethoxy)-acetylamino]-3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-methanesulfonylamino-3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-3-(pyridine-3-sulfonylamino)-propionic acid;
3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-3-(1-methyl-5H-imidazole-4-sulfonylamino)-propionic acid;
3-acetylamino-3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-propionic acid;
3-(3,4-dimethoxy-benzoylamino)-3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)pyridin-3-yl]-propionic acid;
N-{2-carboxy-1-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-ethyl}-terephthalamic acid;
3-benzoylamino-3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-propionic acid;
3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-3-[(tetrahydro-pyran-4-carbonyl)-amino]-propionic acid;
3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-3-[(pyridazine-3-carbonyl)-amino]-propionic acid;
3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-3-[(thiophene-2-carbonyl)-amino]-propionic acid;
N-{2-carboxy-1-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-ethyl}-succinamic acid;
4-{2-carboxy-1-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-ethylcarbamoyl}-butyric acid;
3-(2-amino-acetylamino)-3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-propionic acid;
3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-3-(2-morphol in-4-yl-acetylamino)-propionic acid;
3-[2-(2-methoxy-ethoxy)-acetylamino]-3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-propionic acid;
3-methanesulfonylamino-3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl }-methyl-amino)-pyridin-3-yl]-propionic acid;
3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-3-(pyridine-3-sulfonylamino)-propionic acid;
3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-3-(1-methyl-5H-imidazole-4-sulfonylamino)-propionic acid;
3-(acetyl-methyl-amino)-3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-[(3,4-dimethoxy-benzoyl)-methyl-amino]-3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)-phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
N-[2-carboxy-1-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-ethyl]-N-methyl-terephthalamic acid;
3-(benzoyl-methyl-amino)-3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-3-[methyl-(tetrahydro-pyran-4-carbonyl)-amino]-propionic acid;
3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-3-[methyl-(pyridazine-3-carbonyl)-amino]-propionic acid;
3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-3-[methyl-(thiophene-2-carbonyl)-amino]-propionic acid;
N-[2-carboxy-1-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-ethyl]-N-methyl-succinamic acid;
4-{[2-carboxy-1-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-ethyl]-methyl-carbamoyl}-butyric acid;
3-(aminoacetyl-methyl-amino)-3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-3-[methyl-(morpholin-4-yl-acetyl)-amino]-propionic acid;
3-{[(2-methoxy-ethoxy)-acetyl]-methyl-amino}-3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-(methanesulfonyl-methyl-amino)-3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino)}-pyridin-3-yl)-3-[methyl-(pyridine-3-sulfonyl)-amino]-propionic acid;
3-(6-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-3-[methyl-(1-methyl-5H-imidazole-4-sulfonyl)-amino]-propionic acid;
3-acetylamino-3-(6-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-(3,4-dimethoxy-benzoylamino)-3-(6-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
N-[2-carboxy-1-(6-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-ethyl]-terephthalamic acid;
3-benzoylamino-3-(6-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-[(tetrahydro-pyran-4-carbonyl)-amino]-3-(6-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-[(pyridazine-3-carbonyl)-amino]-3-(6-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-[(thiophene-2-carbonyl)-amino]-3-(6-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
N-[2-carboxy-1-(6-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-ethyl]-succinamic acid;
4-[2-carboxy-1-(6-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-ethylcarbamoyl]-butyric acid;
3-(2-amino-acetylamino)-3-(6-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-(2-morpholin-4-yl-acetylamino)-3-(6-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-[2-(2-methoxy-ethoxy)-acetylamino]-3-(6-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-methanesulfonylamino-3-(6-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-(pyridine-3-sulfonylamino)-3-(6-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-(1-methyl-5H-imidazole-4-sulfonylamino)-3-(6-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-3-yl)-propionic acid;
3-(acetyl-methyl-amino)-3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-propionic acid;
3-[(3,4-dimethoxy-benzoyl)-methyl-amino]-3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-propionic acid;
N-{2-carboxy-1-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-ethyl}-N-methyl-terephthalamic acid;
3-(benzoyl-methyl-amino)-3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)pyridin-3-yl]-propionic acid;
3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-3-[methyl-(tetrahydro-pyran-4-carbonyl)-amino]-propionic acid;
3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-3-[methyl-(pyridazine-3-carbonyl)-amino]-propionic acid;
3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-3-[methyl-(thiophene-2-carbonyl)-amino]-propionic acid;
N-{2-carboxy-1-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-ethyl}-N-methyl-succinamic acid;
4-({2-carboxy-1-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-ethyl}-methyl-carbamoyl)-butyric acid;
3-(aminoacetyl-methyl-amino)-3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)pyridin-3-yl]-propionic acid;
3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-3-[methyl-(morpholin-4-yl-acetyl)-amino]-propionic acid;
3-{[(2-methoxy-ethoxy)-acetyl]-methyl-amino}-3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)-phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-propionic acid;
3-(methanesulfonyl-methyl-amino)-3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-propionic acid;
3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-3-[methyl-(pyridine-3-sulfonyl)-amino]-propionic acid;
3-[6-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-3-yl]-3-[methyl-(1-methyl-5H-imidazole-4-sulfonyl)-amino]-propionic acid;
3-acetylamino-3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid.
3-(3,4-dimethoxy-benzoylamino)-3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
N-[2-carboxy-1-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-ethyl]-terephthalamic acid;
3-benzoylamino-3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino)}-pyridin-2-yl)-3-[(tetrahydropyran-4-carbonyl)-amino]-propionic acid;
3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-3-[(pyridazine-3-carbonyl)-amino]-propionic acid;
3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-3-[(thiophene-2-carbonyl)-amino]-propionic acid;
N-[2-carboxy-1-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-ethyl]-succinamic acid;
4-[2-carboxy-1-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-ethylcarbamoyl]-butyric acid;
3-(2-amino-acetylamino)-3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-3-(2-morpholin-4-yl-acetylamino)-propionic acid;
3-[2-(2-methoxy-ethoxy)-acetylamino]-3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-methanesulfonylamino-3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-3-(pyridine-3-sulfonylamino)-propionic acid;
3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-3-(1-methyl-5H-imidazole-4-sulfonylamino)-propionic acid;
3-acetylamino-3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-propionic acid;
3-(3,4-dimethoxy-benzoylamino)-3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-propionic acid;
N-{2-carboxy-1-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-ethyl}-terephthalamic acid;
3-benzoylamino-3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-propionic acid;
3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-3-[(tetrahydro-pyran-4-carbonyl)-amino]-propionic acid;
3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-3-[(pyridazine-3-carbonyl)-amino]-propionic acid;
3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-3-[(thiophene-2-carbonyl)-amino]-propionic acid;
N-{2-carboxy-1-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-ethyl}-succinamic acid;
4-{2-carboxy-1-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-ethylcarbamoyl}-butyric acid;
3-(2-amino-acetylamino)-3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)pyridin-2-yl]-propionic acid;
3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-3-(2-morpholin-4-yl-acetylamino)-propionic acid;
3-[2-(2-methoxy-ethoxy)-acetylamino]-3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-propionic acid;
3-methanesulfonylamino-3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-propionic acid;
3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-3-(pyridine-3-sulfonylamino)-propionic acid;
3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-3-(1-methyl-5H-imidazole-4-sulfonylamino)-propionic acid;
3-(acetyl-methyl-amino)-3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-[(3,4-dimethoxy-benzoyl)-methyl-amino]-3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)-phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
N-[2-carboxy-1-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-ethyl]-N-methyl-terephthalamic acid;
3-(benzoyl-methyl-amino)-3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-3-[methyl-(tetrahydro-pyran-4-carbonyl)-amino]-propionic acid;
3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-3-[methyl-(pyridazine-3-carbonyl)-amino]-propionic acid;
3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-3-[methyl-(thiophene-2-carbonyl)-amino]-propionic acid;
N-[2-carboxy-1-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-ethyl]-N-methyl-succinamic acid;
4-{[2-carboxy-1-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-ethyl]-methyl-carbamoyl}-butyric acid;
3-(aminoacetyl-methyl-amino)-3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-3-[methyl-(morpholin-4-yl-acetyl)-amino]-propionic acid;
3-{[(2-methoxy-ethoxy)-acetyl]-methyl-amino}-3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-(methanesulfonyl-methyl-amino)-3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-3-[methyl-(pyridine-3-sulfonyl)-amino]-propionic acid;
3-(5-{2-[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-3-[methyl-(1-methyl-5H-imidazole-4-sulfonyl)-amino]-propionic acid;
3-acetylamino-3-(5-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-(3,4-dimethoxy-benzoylamino)-3-(5-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
N-[2-carboxy-1-(5-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-ethyl]-terephthalamic acid;
3-benzoylamino-3-(5-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-[(tetrahydro-pyran-4-carbonyl)-amino]-3-(5-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-[(pyridazine-3-carbonyl)-amino]-3-(5-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-[(thiophene-2-carbonyl)-amino]-3-(5-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
N-[2-carboxy-1-(5-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-ethyl]-succinamic acid;
4-[2-carboxy-1-(5-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-ethylcarbamoyl]-butyric acid;
3-(2-amino-acetylamino)-3-(5-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-(2-morpholin-4-yl-acetylamino)-3-(5-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-[2-(2-methoxy-ethoxy)-acetylamino]-3-(5-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-methanesulfonylamino-3-(5-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-(pyridine-3-sulfonylamino)-3-(5-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-(1-methyl-5H-imidazole-4-sulfonylamino)-3-(5-{2-[4-(3-(2-methylphenyl)ureido)phenyl]-acetylamino}-pyridin-2-yl)-propionic acid;
3-(acetyl-methyl-amino)-3-[5-({[3-methoxy-4-(3-(2-methylphenyl)urido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-propionic acid;
3-[(3,4-dimethoxy-benzoyl)-methyl-amino]-3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)-phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-propionic acid;
N-{2-carboxy-1-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-ethyl}-N-methyl-terephthalamic acid;
3-(benzoyl-methyl-amino)3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-propionic acid;
3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-3-[methyl-(tetrahydro-pyran-4-carbonyl)-amino]-propionic acid;
3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-3-[methyl-(pyridazine-3-carbonyl)-amino]-propionic acid;
3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-3-[methyl-(thiophene-2-carbonyl)-amino]-propionic acid;
N-{2-carboxy-1-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-ethyl}-N-methyl-succinamic acid;
4-({2-carboxy-1-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-ethyl}-methyl-carbamoyl)-butyric acid;
3-(aminoacetyl-methyl-amino)-3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-propionic acid;
3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-3-[methyl-(morpholin-4-yl-acetyl)-amino]-propionic acid;
3-{[(2-methoxy-ethoxy)-acetyl]-methyl-amino}-3-[5-({[3-methoxy-4-(3-(2-methylphenyl(ureido)-phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-propionic acid;
3-(methanesulfonyl-methyl-amino)-3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-propionic acid;
3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-3-[methyl-(pyridine-3-sulfonyl)-amino]-propionic acid;
3-[5-({[3-methoxy-4-(3-(2-methylphenyl)ureido)phenyl]-acetyl}-methyl-amino)-pyridin-2-yl]-3-[methyl-(1-methyl-5H-imidazole-4-sulfonyl)-amino]-propionic acid;
3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-3-(methanesulphonylamino)-propanoic acid;
3-(acetylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-(benzoylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-3-(3-pyridylacetylamino)-propanoic acid;
3-amino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-(n-butylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-benzylamino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-3-(2-phenylethylamino)-propanoic acid;
3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-3-(morpholin-4-yl)-propanoic acid;
3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-3-(4-methylpiperazin-1-yl)propanoic acid;
3-(N-acetyl-N-methylamino)-3-(4-{4-[3-(2-methylphenyl)ureido]phenylacetyl-N-methylamino}-phenyl)-propionic acid;
3-benzyloxycarbonylamino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid;
3-phenylsulphonylamino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid;
3-(pyridine-3-carbonylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetyl-amino}phenyl)-propanoic acid;
3-(pyridine-3-sulphonylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetyl-amino}phenyl)-propanoic acid;
3-(5-dimethylamino-1-naphthalenesulphonylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)-ureido]phenylacetylamino}phenyl)-propanoic acid;
3-(4-carboxybutanoylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid;
3-(3-carboxypropanoylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-(1-methylimidazol-4-ylsulphonylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-(N-acetyl-methylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid;
3-(N-methanesulphonyl-methylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-(morpholin-1-ylacetylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-acetylamino-3-(4-{3-methylthio-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-acetylamino-3-(4-{3-methylsulphinyl-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-acetylamino-3-(4-{3-methylsulphonyl-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid;
3-[2-(2-methoxyethoxy)acetylamino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-[(tetrahydropyran-4-carbonyl)amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-[(5-methyl-isoxazole-3-carbonyl)amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-[(thiophene-2-carbonyl)-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-[(4-carboxybenzoyl)-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-[(pyridazin-3-carbonyl)-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-[(3,4-dimethoxybenzoyl)-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-[(pyridazin-3-carbonyl)-amino]-3-(4-{4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-(4-carboxy-3,3-dimethyl-butanoylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid;
3-(benzoylamino)-3-(4-{4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-(4-carboxybutanoylamino)-3-(4-{4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid;
3-[4-({3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetyl}-N-methylamino)-phenyl]-butanoic acid;
3-[(4-carboxypyridine-3-carbonyl)-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-[2,2-di-(hydroxymethyl)propanoyl-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}phenyl)-propanoic acid;
3-[2-(carboxymethyloxy)-acetylamino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-[(1-carboxymethyl-piperidin-4-carbonyl)-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-[2-(4-methyl-piperazin-1-yl)-acetylamino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}phenyl)-propanoic acid;
3-(pyrrolidin-1-yl)-3-[4-({4-[3-(2-methylphenyl)ureido]phenylacetyl}-methylamino)-phenyl]-propanoic acid;
3-(N-acetyl-methylamino)-3-[4-({4-[3-(2-methylphenyl)ureido]phenylacetyl}-methylamino)-phenyl]-propanoic acid;
3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-5-(4-methylpiperazin-1-yl)-5-oxo-pentanoic acid;
3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-5-(morpholin-4-yl)-5-oxo-pentanoic acid;
and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Preferred compounds of the invention include:
3-(5-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}pyrid-2-yl)-propanoic acid;
3-(6-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}pyrid-3-yl)-propanoic acid;
3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-3-(methanesulphonylamino)-propanoic acid;
3-(acetylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-(benzoylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-3-(3-pyridylacetylamino)-propanoic acid;
3-amino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-(n-butylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-benzylamino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-3-(2-phenylethylamino)-propanoic acid;
3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-3-(morpholin-4-yl)-propanoic acid;
3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-3-(4-methylpiperazin-1-yl)-propanoic acid;
3-(N-acetyl-N-methylamino)-3-(4-{4-[3-(2-methylphenyl)ureido]phenylacetyl-N-methylamino}phenyl)-propionic acid;
3-benzyloxycarbonylamino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)propanoic acid;
3-phenylsulphonylamino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid;
3-(pyridine-3-carbonylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-(pyridine-3-sulphonylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-(5-dimethylamino-1-naphthalenesulphonylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-(4-carboxybutanoylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid;
3-(3-carboxypropanoylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-(1-methylimidazol-4-ylsulphonylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-(N-acetyl-methylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid;
3-(N-methanesulphonyl-methylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-(morpholin-1-ylacetylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-acetylamino-3-(4-{3-methylthio-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid
3-acetylamino-3-(4-{3-methylsulphinyl-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-acetylamino-3-(4-{3-methylsulphonyl-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid;
3-[2-(2-methoxyethoxy)acetylamino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]acetylamino}phenyl)-propanoic acid;
3-[(tetrahydropyran-4-carbonyl)amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-[(5-methyl-isoxazole-3-carbonyl)-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-[(thiophene-2-carbonyl)-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-[(4-carboxybenzoyl)-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-[(pyridazin-3-carbonyl)amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-[(3,4-dimethoxybenzoyl)-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
3-[(pyridazin-3-carbonyl)-amino]-3-(4-{4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-(4-carboxy-3,3-dimethyl-butanoylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}-phenyl)-propanoic acid;
3-(benzoylamino)-3-(4-{4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
3-(4-carboxybutanoylamino)-3-(4-{4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid;
3-[4-({3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetyl}-N-methylamino)-phenyl]-butanoic acid;
3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-5-(4-methylpiperazin-1-yl)-5-oxo-pentanoic acid;
3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-5-(morpholin-4-yl)-5-oxo-pentanoic acid;
and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Especially preferred compounds of the invention include:
(R)-3-acetylamino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
(R)-3-(4-carboxybutanoylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
(R)-3-(3-carboxypropanoylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
(R)-3-(pyridine-3-carbonylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
(R)-3-benzoylamino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
(R)-3-[2-(2-methoxyethoxy)acetylamino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
(R)-3-[(tetrahydropyran-4-carbonyl)amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}phenyl)-propanoic acid;
(R)-3-[(5-methyl-isoxazole-3-carbonyl)-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}phenyl)-propanoic acid;
(R)-3-[(thiophene-2-carbonyl)-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
(R)-3-[(4-carboxybenzoyl)-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
(R)-3-[(pyridazin-3-carbonyl)-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
(R)-3-[(3,4-dimethoxybenzoyl)-amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid;
(R)-3-[(pyridazin-3-carbonyl)-amino]-3-(4-{4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid;
(R)-3-(4-carboxy-3,3-dimethyl-butanoylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}-phenyl)-propanoic acid;
(R)-3-(benzoylamino)-3-(4-{4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid;
(R)-3-(4-carboxybutanoylamino)-3-(4-{4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid;
and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
The compounds of the invention exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. The present invention thus provides, according to a further aspect, compounds of the invention and compositions containing compounds of the invention for use in therapy.
Compounds within the scope of the present invention block the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (xcex14xcex21) according to tests described in the literature and described in vitro and in vivo procedures hereinafter, and which tests results are believed to correlate to pharmacological activity in humans and other mammals. Thus, in a further embodiment, the present invention provides compounds of the invention and compositions containing compounds of the invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of xcex14xcex21 mediated cell adhesion. For example, compounds of the present invention are useful in the treatment of inflammatory diseases, for example joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis. Additionally, the compounds are useful in the treatment of acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, collitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, multiple sclerosis, asthma, psoriasis restenosis, myocarditis, inflammatory bowel disease and melanoma cell division in metastasis.
A special embodiment of the therapeutic methods of the present invention is the treating of asthma.
Another special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.
Another special embodiment of the therapeutic methods of the present invention is the treating of inflammatory bowel disease.
According to a further feature of the invention there is provided a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (xcex14xcex21), for example conditions as hereinbefore described, which comprises the administration to the patient of an effective amount of compound of the invention or a composition containing a compound of the invention. xe2x80x9cEffective amountxe2x80x9d is meant to describe an amount of compound of the present invention effective in inhibiting the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (xcex14xcex21), and thus producing the desired therapeutic effect.
References herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions.
The present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of the invention in association with a pharmaceutically acceptable carrier or excipient.
Compounds of the invention may be administered by any suitable means. In practice compounds of the present invention may generally be administered parenterally, topically, rectally, orally or by inhalation, especially by the oral route.
Compositions according to the invention may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavourings, colourings, or stabilisers in order to obtain pharmaceutically acceptable preparations. The choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the active compound, the particular mode of administration and the provisions to be observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used for preparing tablets. To prepare a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
For parenteral administration, emulsions, suspensions or solutions of the products according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilised by heating, irradiation or microfiltration.
For topical administration, gels (water or alcohol based), creams or ointments containing compounds of the invention may be used. Compounds of the invention may also be incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.
For administration by inhalation compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebuliser or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention.
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
The compounds according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one or two doses per day.
Compounds of the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.
In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991.
Compounds of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the Y moiety within one of X3, X4 and X5 is carboxy, may be prepared by hydrolysis of esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the Y moiety within one of X3, X4 and X5 is a xe2x80x94CO2R16 group (in which R16 is alkyl, alkenyl or arylalkyl). The hydrolysis may conveniently be carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide, e.g. lithium hydroxide, or an alkali metal carbonate, e.g. potassium carbonate, in the presence of an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol, at a temperature from about ambient to about reflux. The hydrolysis of the esters may also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50xc2x0 C. to about 80xc2x0 C.
As another example compounds of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the Y moiety within one of X3, X4 and X5 is carboxy, may be prepared by acid catalysed removal of the tert-butyl group of tert-butyl esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined; and where the Y moiety within one of X3, X4 and X5 is a xe2x80x94CO2R16 group (in which R16 is tert-butyl), using standard reaction conditions, for example reaction with trifluoroacetic acid at a temperature at about room temperature.
As another example compounds of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the Y moiety within one of X3, X4 and X5 is carboxy, may be prepared by hydrogenation of compounds of formula (I) wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the Y moiety within one of X3, X4 and X5 is a xe2x80x94CO2R16 group (in which R16 is benzyl). The reaction may be carried out in the presence of ammonium formate and a suitable metal catalyst, e.g. palladium, supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol and at a temperature at about reflux temperature. The reaction may alternatively be carried out in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol. This reaction is most suitable for compounds of formula (I) where L1 and L2 do not contain carbon-carbon multiple bonds.
As another example compounds of formula (Ia) or (Ib), wherein R1, R2,Ar1, L2, X1 and X2 are as hereinbefore defined, X3 is CR10 (where R10 is as hereinbefore defined), and Y is carboxy, represented by formula (II), may be prepared by using resin technology as shown in scheme 1. 
For example Wang resin may be treated, in Step 1, with acids of formula (III):
xe2x80x83O2Nxe2x80x94Ar1xe2x80x94L2xe2x80x94CO2Hxe2x80x83xe2x80x83(III)
wherein Ar1 and L2 are as hereinbefore defined, with diisopropyl carbodiimide in dimethylformamide, in the presence of dimethylaminopyridine, at room temperature. The resulting esters (Resin 2), wherein Ar1 and L2 are as hereinbefore defined, may then treated, in Step 2, with tin chloride in dimethylformamide at room temperature to give Resin 3, wherein Ar1 and L2 are as hereinbefore defined. Resin 3 may then be coupled, in Step 3, with an acid of general formula (IV): 
wherein R1, R2, X1 and X2 are as hereinbefore, and X3 is CR10 (where R10 is as hereinbefore defined), in the presence of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide, at room temperature. The resulting Resin 4, wherein R1, R2, Ar1, L2, X1 and X2 are as hereinbefore defined , and X3 is CR10 (where R10 is as hereinbefore defined), may then be treated, in Step 4, with trifluoroacetic acid in an inert solvent such as dichloromethane, at room temperature, to liberate the acids of general formula (II), wherein R1, R2, Ar1, L2, X1 and X2 are as hereinbefore defined, and X3 is CR10 (where R10 is as hereinbefore defined).
As another example compounds of formula (Ib), wherein R1, R2, Ar1, X1 and X2 are as hereinbefore defined, L2 is a xe2x80x94Z2xe2x80x94R9xe2x80x94 linkage [in which R9 is as hereinbefore defined and Z2 is O, S or NR4 (where R4 is as defined hereinbefore)], X3 is CR10 (where R10 is as hereinbefore defined), and Y is carboxy, represented by formula (V), may be prepared by using resin technology as shown in scheme 2. 
For example Wang resin in scheme 2 may be treated, in Step 1, with acids of formula (VI):
R17xe2x80x94CO2Hxe2x80x83xe2x80x83(VI)
wherein R17 is Brxe2x80x94R9xe2x80x94 [in which R9 is as hereinbefore defined], with diisopropyl carbodiimide in dimethylformamide or a mixture of dimethylformamide and tetrahydrofuran, in the presence of dimethylaminopyridine, at room temperature. The resulting esters (Resin 5, in which R17 is Brxe2x80x94R9xe2x80x94) may be reacted, in Step 2, with compounds of formula (VII):
H2Nxe2x80x94Ar1xe2x80x94Z2Hxe2x80x83xe2x80x83(VIl)
wherein Ar1 is heteroaryldiyl and Z2 is O, S or NR4 (where R4 is as defined hereinbefore), in the presence of a base, such as a tertiary organic base, for example diisopropylethylamine, in dimethylsulphoxide and at a temperature at about room temperature, to give Resin 6, in which R9 and Ar1 is heteroaryldiyl and Z2 is O, S or NR4 (where R4 is as defined hereinbefore). Resin 6 may then be coupled, in Step 3, with an acid of general formula (IV), wherein R1, R2, X1 and X2 are as hereinbefore defined, and X3 is CR10 (where R10 is as hereinbefore defined), in the presence of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide, at room temperature. The resulting Resin 7 [in which R1, R2, R9, X1 and X2 are as hereinbefore defined, Ar1 is heteroaryldiyl, X3 is CR10 (where R10 is as hereinbefore defined), and Z2 is O, S or NR4 (where R4 is as defined hereinbefore)], may then be treated, in Step 4, with trifluoroacetic acid in an inert solvent such as dichloromethane and at a temperature at about room temperature, to liberate the acids of general formula (V), wherein R1, R2, R9, X1 and X2 are as hereinbefore defined, Ar1 is heteroaryldiyl, X3 is CR10 (where R10 is as hereinbefore defined), and Z2 is O, S or NR4 (where R4 is as defined hereinbefore). This methodology is particularly suited to the preparation of compounds of formula (V) where L2 is a xe2x80x94Sxe2x80x94CH2xe2x80x94 linkage.
As another example, Wang resin in scheme 2 may be treated, in Step 1, with acid chlorides of formula (VIII):
R17xe2x80x94C(xe2x95x90O)xe2x80x94Clxe2x80x83xe2x80x83(VIII)
wherein R17 is a vinyl moiety optionally substituted by R5, in the presence of a tertiary amine, such as diisopropylethylamine, in an inert solvent, such as dichloromethane, at a temperature at about room temperature. The resulting optionally substituted vinyl ester (Resin 5, in which R17 is a vinyl moiety optionally substituted by R5), may then be reacted with compounds of formula (VII), wherein Ar1 is heteroaryldiyl and Z2 is S, in the presence of a base, such as a tertiary organic base, for example diisopropylethylamine, in dimethylsulphoxide and at a temperature at about room temperature, to give Resin 6 [in which Ar1 is heteroaryldiyl, R9 is ethylene (optionally substituted by R5) and Z2 is S]. Resin 6 may then be coupled with an acid of general formula (IV), wherein R1, R2, X1 and X2 are as hereinbefore defined, and X3 is CR10 (where R10 is as hereinbefore defined), in the presence of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide, at room temperature. The resulting Resin 7 [in which R1, R2, X1 and X2 are as defined hereinbefore, Ar1 is heteroaryldiyl, R9 is ethylene (optionally substituted by R5), X3 is CR10 (where R10 is as hereinbefore defined), and Z2 is S], may then be treated with trifluoroacetic acid in an inert solvent such as dichloromethane and at a temperature at about room temperature, to liberate the acids of general formula (V), wherein R1, R2, X1 and X2 are as defined hereinbefore, Ar1 is heteroaryldiyl, R9 is ethylene (optionally substituted by R5), X3 is CR10 (where R10 is as hereinbefore defined), and Z2 is S.
As another example compounds of formula (Ia) or (Ib), wherein R1, R2, L2, Ar1, X1 and X2 are as hereinbefore defined, and X3 is CR10 (where R10 is as hereinbefore defined), and Y is carboxy, may be prepared by coupling acids of formula (IV), wherein R1, R2, X1 and X2 are as hereinbefore, and X3 is CR10 (where R10 is as hereinbefore defined), with amines of formula (IX):
H2Nxe2x80x94Ar1xe2x80x94L2xe2x80x94CO2Hxe2x80x83xe2x80x83(IX)
wherein Ar1 and L2 are as hereinbefore defined, using standard coupling conditions, for example those hereinbefore described.
As another example compounds of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L2 and Y moieties within one of X3, X4 and X5 are an alkylene linkage substituted by xe2x80x94CONY1Y2 and carboxy respectively, may be prepared by reaction of compounds of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L2 and Y moieties within one of X3, X4 and X5 are an alkylene linkage substituted by xe2x80x94CO2H and carboxy respectively, with an anhydride, such as trifluoroacetic anhydride, in an inert solvent e.g. tetrahydrofuran, followed by treatment with an amine HNY1Y2.
According to a further feature of the present invention, compounds of the invention may be prepared by interconversion of other compounds of the invention.
For example compounds of formula (I) wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the Y moiety within one of X3, X4 and X5 is xe2x80x94C(xe2x95x90O)xe2x80x94NHOH, may be prepared by reaction of compounds of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, and where the Y moiety within one of X3, X4 and X5 is carboxy, with hydroxylamine using standard peptide coupling procedures such as treatment with a carbodiimide, for example dicyclohexylcarbodiimide, in the presence of triethylamine, in an inert solvent such as dichloromethane or tetrahydrofuran and at a temperature at about room temperature. The coupling may also be carried out using 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in dichloromethane at room temperature. The preparation may also be carried out using an O-protected hydroxylamine such as O-(trimethylsilyl)hydroxylamine, O-(t-butyldimethylsilyl)-hydroxylamine, or O-(tetrahydropyranyl)hydroxylamine followed by treatment with acid.
As another example of the interconversion process, compounds of formula (I) containing sulphoxide linkages may be prepared by the oxidation of corresponding compounds containing xe2x80x94Sxe2x80x94 linkages. For example, the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature, or alternatively by means of potassium hydrogen peroxomonosulphate in a medium such as aqueous methanol, buffered to about pH5, at temperatures between about 0xc2x0 C. and room temperature. This latter method is preferred for compounds containing an acid-labile group.
As another example of the interconversion process, compounds of formula (I) containing sulphone linkages may be prepared by the oxidation of corresponding compounds containing xe2x80x94Sxe2x80x94 or sulphoxide linkages. For example, the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature.
As another example of the interconversion process, compounds of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore described and the L2 moiety within one of X3, X4 and X5 is an optionally substituted alkylene linkage, may be prepared by hydrogenation of the corresponding compounds of formula (I) in which the L2 moiety within one of X3, X4 and X5 is the corresponding optionally substituted alkenylene linkage. The hydrogenation may be carried out using hydrogen (optionally under pressure) in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol, and at a temperature at about room temperature.
As another example of the interconversion process, compounds of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore described and the L1 moiety within one of X3, X4 and X5 is a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage where R2 is a straight or branched chain C2-6alkylene chain and R3 is a direct bond, may be similarly prepared by hydrogenation of the corresponding compounds of formula (I) in which the L1 moiety within one of X3, X4 and X5 is a xe2x80x94R2xe2x80x94R3 linkage where R2 is a straight or branched chain C2-6alkenylene chain and R3 is a direct bond.
As another example of the interconversion process, compounds of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore described, and where the L2 moiety within one of X3, X4 and X5 contains an amino group, may be prepared by treatment of compounds of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore described, and the L2 moiety within one of X3, X4 and X5 contains an acetamido group, with a base, such as an aqueous alkali metal hydroxide, for example sodium hydroxide.
As another example of the interconversion process, compounds of the invention containing a heterocyclic group wherein the hetero atom is a nitrogen atom may be oxidised to their corresponding N-oxides. The oxidation may conveniently be carried out by means of reaction with a mixture of hydrogen peroxide and an organic acid, e.g. acetic acid, preferably at or above room temperature, for example at a temperature of about 60-90xc2x0 C. Alternatively, the oxidation may be carried out by reaction with a peracid, for example peracetic acid or m-chloroperoxybenzoic acid, in an inert solvent such as chloroform or dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature. The oxidation may alternatively be carried out by reaction with hydrogen peroxide in the presence of sodium tungstate at temperatures between room temperature and about 60xc2x0 C.
It will be appreciated that compounds of the present invention may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallisation techniques, or they are separately prepared from the appropriate isomers of their intermediates.
According to a further feature of the invention, acid addition salts of the compounds of this invention may be prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention may be prepared either by dissolving the free base in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
Compounds of this invention can be regenerated from their base addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
Compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol.
According to a further feature of the invention, base addition salts of the compounds of this invention may be prepared by reaction of the free acid with the appropriate base, by the application or adaptation of known methods. For example, the base addition salts of the compounds of this invention may be prepared either by dissolving the free acid in water or aqueous alcohol solution or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The starting materials and intermediates may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L1 and Y moieties within one of X3, X4 and X5 are a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage (in which R2 is as hereinbefore defined and R3 is xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94) and a xe2x80x94CO2R16 group (in which R16 is as hereinbefore defined ) respectively, may be prepared by reaction of compounds of formula (1): 
wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 [in which R18 is xe2x80x94R2xe2x80x94C(xe2x95x90O)X10 (where R2 is as hereinbefore defined and X10 is a hydroxy group, or a halogen, preferably chlorine, atom)] and the others independently represent N or CR10 (where R10 is as hereinbefore defined), with amines of formula (2):
R4xe2x80x94HNxe2x80x94Ar1xe2x80x94L2xe2x80x94CO2R16xe2x80x83xe2x80x83(2)
wherein R4, R16, Ar1 and L2 are as hereinbefore defined. When X10 is a hydroxy group the reaction may be carried out using standard peptide coupling procedures as described hereinbefore. When X10 is a halogen atom the reaction may be carried out with the aid of a base, such pyridine, preferably in a solvent such as tetrahydrofuran and at a temperature at about room temperature.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L1 and Y moieties within one of X3, X4 and X5 are a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage [in which R2 is as hereinbefore defined and R3 is xe2x80x94NR4xe2x80x94C(xe2x95x90O)xe2x80x94 (where R4 is as hereinbefore defined)] and a xe2x80x94CO2R16 group (in which R16 is as hereinbefore defined) respectively, may be prepared by reaction of compounds of formula (1), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 [in which R18 is xe2x80x94R2xe2x80x94NHR4 (where R2 and R4 are as hereinbefore defined)] and the others independently represent N or CR10 (where R10 is as hereinbefore defined), with compounds of formula (3):
X10xe2x80x94C(xe2x95x90O)xe2x80x94Ar1xe2x80x94L2xe2x80x94CO2R66xe2x80x83xe2x80x83(3)
wherein R16, Ar1, L2 and X10 are as hereinbefore defined, using procedures described hereinbefore for coupling acids or acid halides with amines.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L1 and Y moieties within one of X3, X4 and X5 groups are a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage [in which R2 is as hereinbefore defined and R3 is xe2x80x94Oxe2x80x94] and a xe2x80x94CO2R16 group (in which R16 is as hereinbefore defined) respectively, may be prepared by reaction of compounds of formula (1), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 (in which R18 is xe2x80x94R2xe2x80x94OH) and the others independently represent N or CR10 (where R10 is as hereinbefore defined), with compounds of (4):
HOxe2x80x94Ar1xe2x80x94L2xe2x80x94CO2R16xe2x80x83xe2x80x83(4)
wherein R16, Ar1 and L2 are as hereinbefore defined, in the presence of a dialkyl azodicarboxylate, such as diethyl azodicarboxylate, and triphenylphosphine, preferably in a dry ethereal solvent, e.g. diethyl ether or tetrahydrofuran, preferably at or near room temperature.
Alternatively esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L1 and Y moieties within one of X3, X4 and X5 are a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage [in which R2 is as hereinbefore defined and R3 is xe2x80x94Oxe2x80x94] and a xe2x80x94CO2R16 group (in which R16 is as hereinbefore defined) respectively, may also be prepared by alkylation of compounds of formula (4), wherein R16, Ar1 and L2 are as hereinbefore defined. The reaction may be carried using standard alkylation conditions for example reaction with the appropriate alkyl bromides of formula (1), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 [in which R18 is xe2x80x94R2xe2x80x94Br (where R2 is as hereinbefore defined)], and the others independently represent N or CR10 (where R10 is as hereinbefore defined).
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L1 and Y moieties within one of X3, X4 and X5 are a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage [in which R2 is as hereinbefore defined and R3 is xe2x80x94Sxe2x80x94] and a xe2x80x94CO2R16 group (in which R16 is as hereinbefore defined) respectively, may be similarly prepared by alkylation of compounds of formula (5):
HSxe2x80x94Ar1xe2x80x94L2xe2x80x94CO2R16xe2x80x83xe2x80x83(5)
wherein R16, Ar1 and L2 are as hereinbefore defined.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L1 and Y moieties within one of X3, X4 and X5 are a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage [in which R2 is as hereinbefore defined and R3 is xe2x80x94NR4xe2x80x94 (where R4 is as hereinbefore defined)] and a xe2x80x94CO2R16 group (in which R16 is as hereinbefore defined) respectively, may be similarly prepared by alkylation of compounds of formula (2), wherein R4, R16, Ar1 and L2 are as hereinbefore defined.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L1 and Y moieties within one of X3, X4 and X5 are a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage [in which R2 is as hereinbefore defined and R3 is xe2x80x94C(xe2x95x90O)xe2x80x94] and a xe2x80x94CO2R16 group (where R16 is as hereinbefore defined) respectively, may be prepared by reaction of compounds of formula (1), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 [in which R18 is xe2x80x94R2xe2x80x94CO2R16 (where R2 and R16 are as hereinbefore defined)], and the others independently represent N or CR10 (where R10 is as hereinbefore defined), with Grignard reagents derived from reaction of compounds of formula (6):
Brxe2x80x94Ar1xe2x80x94L2xe2x80x94CO2R16xe2x80x83xe2x80x83(6)
wherein R16, Ar1 and L2 are as hereinbefore defined, with magnesium using standard reaction conditions.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L1 and Y moieties within one of X3, X4 and X5 are a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage [in which R2 is as hereinbefore defined and R3 is xe2x80x94NR4xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 (where R4 is as hereinbefore defined)] and a xe2x80x94CO2R16 group (where R16 is as hereinbefore defined) respectively, may be prepared by reaction of compounds of formula (1), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 [in which R18 is xe2x80x94R2xe2x80x94NHR4 (where R2 and R4 are as hereinbefore defined)],), and the others independently represent N or CR10 (where R10 is as hereinbefore defined), with isocyanates of formula (7):
Oxe2x95x90Cxe2x95x90Nxe2x80x94Ar1xe2x80x94L2xe2x80x94CO2R16xe2x80x83xe2x80x83(7)
wherein R16, Ar1 and L2 are as hereinbefore defined. The reaction is preferably carried out with the aid of a base, such as a tertiary amine, for example triethylamine, preferably in a solvent such as dichloromethane, and at a temperature at about room temperature.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L1 and Y moieties within one of X3, X4 and X5 are a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage [in which R2 is as hereinbefore defined and R3 is xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NR4xe2x80x94 (where R4 is as hereinbefore defined)] and a xe2x80x94CO2R16 group (where R16 is as hereinbefore defined) respectively, may be similarly prepared by reaction of amines of formula (2), wherein R4, R16, Ar1 and L2 are as hereinbefore defined, with compounds of formula (1), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 [in which R18 is xe2x80x94R2xe2x80x94Nxe2x95x90Cxe2x95x90O (where R2 is as hereinbefore defined)], and the others independently represent N or CR10 (where R10 is as hereinbefore defined).
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L1 and Y moieties within one of X3, X4 and X5 are a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage [in which R2 is as hereinbefore defined and R3 is xe2x80x94SO2xe2x80x94NR4xe2x80x94 (where R4 is as hereinbefore defined)] and a xe2x80x94CO2R16 group (where R16 is as hereinbefore defined) respectively, may be prepared by reaction of compounds of formula (1), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 [in which R18 is xe2x80x94R2xe2x80x94SO2Cl (where R2 is as hereinbefore defined), and the others independently represent N or CR10 (where R10 is as hereinbefore defined), with amines of formula (2) wherein R4, R16, Ar1 and L2 are as hereinbefore defined. The reaction is preferably carried out with the aid of a base, such as a tertiary amine, for example triethylamine, preferably in a solvent such as tetrahydrofuran and at a temperature at about room temperature.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L1 and Y moieties within one of X3, X4 and X5 are a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage [in which R2 is as hereinbefore defined and R3 is xe2x80x94NR4xe2x80x94SO2xe2x80x94 (where R4 is as hereinbefore defined)] and a xe2x80x94CO2R16 group (where R16 is as hereinbefore defined) respectively, may be similarly prepared by reaction of compounds of formula (1), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 [in which R18 is xe2x80x94R2xe2x80x94NHR4 (where R2 and R4 are as hereinbefore defined)], and the others independently represent N or CR10 (where R10 is as hereinbefore defined), with sulphonyl chlorides of formula (8):
Clxe2x80x94SO2xe2x80x94Ar1xe2x80x94L2xe2x80x94CO2R16xe2x80x83xe2x80x83(8)
wherein R16, Ar1 and L2 are as hereinbefore defined.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L1 and Y moieties within one of X3, X4 and X5 are a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage [in which R2 is as hereinbefore defined and R3 is xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94] and a xe2x80x94CO2R16 group (where R16 is as hereinbefore defined) respectively, may be prepared by O-acylation of compounds of formula (1), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 [in which R18 is xe2x80x94R2xe2x80x94OH (where R2 is as hereinbefore defined)], and the others independently represent N or CR10 (where R10 is as hereinbefore defined), with compounds of formula (3), wherein R16, Ar1 and L2 are as hereinbefore defined and X10 is a halogen atom. The reaction may be carried using standard O-acylation conditions for example reaction with acid chlorides of formula (3) where X10 is a chlorine atom.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L1 and Y moieties within one of X3, X4 and X5 are a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage [in which R2 is as hereinbefore defined and R3 is xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94] and a xe2x80x94CO2R16 group (where R16 is as hereinbefore defined) respectively, may be similarly prepared by O-acylation of compounds of formula (4), wherein R16, Ar1 and L2 are as hereinbefore defined with compounds of formula (1), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 [in which R18 is xe2x80x94R2xe2x80x94C(xe2x95x90O)xe2x80x94X10 (where R2 is as hereinbefore defined and X10 is a halogen atom)], and the others independently represent N or CR10 (where R10 is as hereinbefore defined).
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L1 and Y moieties within one of X3, X4 and X5 are a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage [in which R2 is as hereinbefore defined and R3 is xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94] and a xe2x80x94CO2R16 group (where R16 is as hereinbefore defined) respectively, may be prepared by reaction of compounds of formula (1), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 [in which R18 is xe2x80x94R2xe2x80x94OH (where R2 is as hereinbefore defined)], and the others independently represent N or CR10 (where R10 is as hereinbefore defined), with isocyanates of formula (7), wherein R16, Ar1 and L2 are as hereinbefore defined. The reaction is preferably carried out with the aid of a base, such as a tertiary amine, for example triethylamine, preferably in a solvent such as dichloromethane, and at a temperature at about room temperature.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where the L1 and Y moieties within one of X3, X4 and X5 are a xe2x80x94R2xe2x80x94R3xe2x80x94 linkage [in which R2 is as hereinbefore defined and R3 is xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94] and a xe2x80x94CO2R16 group (where R16 is as hereinbefore defined) respectively, may be similarly prepared by reaction of compounds of formula (1), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 [in which R18 is xe2x80x94R2xe2x80x94Nxe2x95x90Cxe2x95x90O (where R2 is as hereinbefore defined)], and the others independently represent N or CR10 (where R10 is as hereinbefore defined), with compounds of formula (4), wherein R16, Ar1 and L2 are as hereinbefore defined.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined and where one of X3, X4 and X5 is Cxe2x80x94R2xe2x80x94R3xe2x80x94Ar1xe2x80x94L2xe2x80x94CO2R16 in which R3 is a direct bond, R2 is a straight or branched chain C2-6alkenylene chain where the carbon-carbon double bond is directly attached to Ar1, and R16 is as hereinbefore defined, may be prepared from compounds of formula (9):
Hxe2x80x94C(xe2x95x90O)xe2x80x94Ar1xe2x80x94L2xe2x80x94CO2R16xe2x80x83xe2x80x83(9)
wherein R16, Ar1 and L2 are as hereinbefore defined, using standard Wittig coupling procedures with an appropriate phosphorane, derived from reaction of the appropriate compounds of formula (1) wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 [in which R18 is xe2x80x94R2xe2x80x94Br (where R2 is a straight or branched chain C1-5alkylene chain)], and the others independently represent N or CR10 (where R10 is as hereinbefore defined), with triphenylphosphine and subsequent treatment with a base using standard procedures.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 is an alkylene linkage substituted by xe2x80x94NY1Y2 (in which one of Y1 and Y2 is hydrogen and the other is alkyl, or alkyl substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, xe2x80x94NY1Y2, or one or more xe2x80x94CO2R12 or xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2 groups), may be prepared by reaction of esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, Y is xe2x80x94CO2R16,and the L2 moiety within one of X3, X4 and X5 is an alkylene linkage substituted by xe2x80x94NH2, with aldehydes of formula (10):
R19xe2x80x94CHOxe2x80x83xe2x80x83(10)
wherein R19 is hydrogen or alkyl, or alkyl substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, xe2x80x94NY1Y2, or one or more xe2x80x94CO2R12 or xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2 groups in the presence of sodium cyanoborohydride. The reaction may be conveniently carried out in methanol, optionally in the presence of sodium acetate and 4 xc3x85 molecular sieves, and at a temperature at about room temperature.
Esters of formula (1), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 contains a xe2x80x94N(R4)xe2x80x94C(xe2x95x90O)xe2x80x94R13 group, may be prepared by reaction of amines of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 contains a xe2x80x94NH(R4) group, with compounds of formula (11):
R13xe2x80x94C(xe2x95x90O)X10xe2x80x83xe2x80x83(11)
wherein R13 and X10 are as hereinbefore defined. When X10 is a hydroxy group the reaction may be carried out using standard peptide coupling procedures as described hereinbefore. When X10 is a halogen atom the reaction may be carried out with the aid of a base, such pyridine, preferably in a solvent such as tetrahydrofuran and at a temperature at about room temperature.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 contains a xe2x80x94N(R4)xe2x80x94C(xe2x95x90O)xe2x80x94OR13 group may be prepared by reaction of amines of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 contains a xe2x80x94NH(R4) group, with the appropriate chloroformate, e.g. ethyl (or benzyl) chloroformate compounds, according to standard reaction conditions.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 contains a xe2x80x94N(R4)xe2x80x94SO2xe2x80x94R13 group, may be prepared by reaction of amines of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 contains a xe2x80x94NH(R4) group,, with the appropriate sulphonyl chloride, e.g. phenyl (or pyrdiyl) sulphonyl chloride, according to standard reaction conditions.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 is a 
linkage, may be prepared by hydrogenation of esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 is a 
linkage. The reaction may be carried out in the presence of formic acid and a suitable metal catalyst, e.g. palladium, supported on an inert carrier such as carbon, at a temperature at about 60xc2x0 C. The reaction may conveniently be carried out in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 is a 
linkage, may be similarly prepared by hydrogenation of esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 is a 
linkage.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 is a 
linkage, may also be obtained following standard recrystallisation of salts of the racemic mixture, for example recrystallisation of the tartrate salt.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 is a 
linkage, may also be obtained by the application of standard enzymatic resolution procedures for example those described by Soloshonok, V. A., et.al., Tetrahedron: Asymmetry 6 (1995) 7, 1601-1610.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 is a 
linkage, may be prepared by reaction of esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined, Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 is a xe2x80x94CHxe2x95x90CHxe2x80x94 linkage, with an alkali metal hydride, such as sodium hydride, in an inert solvent, e.g. tetrahydrofuran, and at a temperature at about room temperature, and subsequent reaction with the anion derived from treating dibenzylamine, or (S)-N-benzyl-(xcex1-methylbenzylamine, with butyllithium, at a temperature at about xe2x88x9278xc2x0 C.
Esters of formula (I), wherein R1, X1, X2, X3, X4, X5 and X6 are as hereinbefore defined Y is xe2x80x94CO2R16 and the L2 moiety within one of X3, X4 and X5 is a xe2x80x94CHxe2x95x90CHxe2x80x94 linkage, may be prepared by reaction of compounds of formula (1), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 [in which R18 is xe2x80x94R2xe2x80x94R3xe2x80x94Ar1xe2x80x94I (where R2, R2 and Ar1 are as hereinbefore defined) and the others independently represent N or CR10 (where R10 is as hereinbefore defined), with an acrylic acid ester, such as tert-butyl acrylate, in the presence of palladium acetate, a triarylphosphine, such as tri(2-methylphenyl)phosphine, and a tertiary amine, such as tributylamine, in an inert solvent, such as dimethylformamide and at a temperature up to about 100xc2x0 C.
Compounds of formula (1), wherein R1, X1, X2 and X6 are as hereinbefore defined, one of X7, X8 and X9 represents Cxe2x80x94R18 (in which R18 is as described hereinabove, or a suitably protected derivative thereof) and the others independently represent N or CR10 (where R10 is as hereinbefore defined), may be prepared by the application or adaptation of methods described in prepared as described in the specification of International Patent Application Publication No. WO 96/22966.
Compounds of formula (2), wherein R16 Ar1 and L2 are as hereinbefore defined and R4 is hydrogen may be prepared by reduction of the corresponding nitro compounds. The reduction may be carried out using iron powder and ammonium chloride, in aqueous ethanol at a temperature at about reflux. The reduction may also be carried out by hydrogenation using standard conditions, for example those described hereinbefore.
Intermediates of formulae (resin 3), (resin 4), (resin 6) and (resin 7) are novel compounds and, as such, they and their processes described herein for their preparation constitute further features of the present invention.
The present invention is further Exemplified but not limited by the following illustrative Examples and Reference Examples.
Mass spectra were recorded on a Micromass Platform II mass spectrometer fitted with an Electrospray source and an HP1100 liquid chromatograph; using a mixture of acetonitrile and water (1:1, v/v) as the mobile phase, a flow rate of 0.3 ml/minute, an injection volume of 20 xcexcl, a run time of 2.0 minutes, a scan range of 150-850 Daltons Positive/Negative, a scan time of 2.0 seconds, an ESI voltage of 3.5 Kv, an ESI pressure of 20 n/m2 Nitrogen.
The ions recorded are positive ions.